A substantial number of cancers fail to respond to conventional radiation and chemotherapy, and thus there exists a clear need for alternative non-surgical strategies. Development of gene therapy techniques is approaching clinical realization for the treatment of neoplastic and metabolic diseases, and numerous genes displaying anti-tumor activity have been identified. However, the usefulness of gene therapy methods has been limited due to systemic toxicity of anti-tumor polypeptides encoded by gene therapy constructs (Spriggs & Yates (1992) in Bentler, ed., Tumor Necrosis Factor: The Molecules and Their Emerging Roles in Medicine, pp. 383–406 Raven Press, New York, N.Y.; Sigel & Puri (1991) J Clin Oncol 9:694–704; Ryffel (1997) Immunopathol 83:18–20). A versatile mechanism for controllable gene expression is therefore highly desired for gene therapy.
A mechanism for controlling gene expression should ideally include both spatial and temporal control of gene expression. One existing strategy employs a chemically regulated signal, for example the tetracycline-inducible gene expression system (Gossen & Bujard (1992) Proc Natl Acad Sci USA 89:5547–5551; Gossen & Bujard (1993) Nuc Acids Res 21(18):4411–4412; Gossen et al. (1995) Science 268:1766–1769). A similar approach involves the provision of ionizing radiation to activate a radiosensitive promoter, e.g. the EGR-1 promoter (Weischelbaum et al. (1994) Cancer Res 54:4266–4269; Hallahan et al. (1995) Nat Med 1(8):786–791; Joki et al. (1995) Hum Gen Ther 6:1507–1513). An alternative design relies on endogenous control of gene expression. For example, the CEA promoter is selectively expressed in cancer cells (Hauck & Stanners (1995) J Biol Chem 270:3602; Richards et al. (1995) Human Gene Ther 6:881–893). Although each of the afore-mentioned systems display inducibility, a lack of temporal and spatial precision of gene induction, an ineffective magnitude of gene induction, a background level of non-induced gene expression, or an inability to regulate termination of gene expression, can still prohibit their usefulness.
Thus, there remains substantial need for improvement of gene therapy methods, particularly with regards to the design of gene therapy constructs adapted for inducible expression and to the development of vector systems for delivery of a therapeutic transgene to target tissues.
To meet this need, the present invention discloses a gene therapy construct comprising a heat-inducible promoter operatively linked to a nucleic acid molecule encoding a polypeptide that can induce immunological and/or anti-angiogenic activity. When employed according to the methods of the present invention, the disclosed gene therapy construct provides precise temporally- and spatially-regulated expression of a therapeutic gene that can promote tumor regression.